Dr. Walker Jackson

Group leader

German Center for Neurodegenerative Diseases (DZNE)
Building 344, BMZ 1
Sigmund-Freud-Str. 25
53127 Bonn

walker.jackson(at)dzne.de
+49 (0) 228 / 287-51704

More information

Group Members Curriculum Vitae

Areas of investigation/research focus

The types of clinical signs present in people suffering from neurodegenerative diseases (NDs) are determined by which brain areas are affected.  For example, areas of the brain important for motor control are damaged in Parkinson’s disease while areas important for memory are damaged in Alzheimer’s disease.  Most NDs appear to be caused by misfolding of proteins and, although there is some variability in the spatial distribution of these disease-causing proteins, there is not a positive correlation between protein levels and the extent of degeneration.  That is, many brain areas express the proteins at relatively high levels but appear to be unaffected.  Why this happens is both a scientifically intriguing question as well as a potential window for the design of therapies.  If we can identify the properties that allow certain cells to naturally tolerate high levels of the misfolded proteins, introduction of these properties into otherwise vulnerable cells may preserve their functionality.

This image highlights the different areas affected in different neurodegenerative diseases. The diseases listed on the top both involve the same protein, PrP, but are caused by different mutations to PrP. The diseases on the bottom both involve the same type of mutation, an expanded glutamine repeat (Q(n), where n > 40 causes disease), but the mutation causes different diseases depending on which protein it is in (for example Htt or Atx1).This image highlights the different areas affected in different neurodegenerative diseases. The diseases listed on the top both involve the same protein, PrP, but are caused by different mutations to PrP. The diseases on the bottom both involve the same type of mutation, an expanded glutamine repeat (Q(n), where n > 40 causes disease), but the mutation causes different diseases depending on which protein it is in (for example Htt or Atx1).Click on the magnifying glass for a large image.

Although there is certainly more to the story, protein expression patterns partially determine which brain regions are affected.  Therefore, it would be ideal to study a set of diseases for which expression pattern differences do not contribute to disease differences.  Prion diseases meet this criteria since misfolding of a single protein can damage brain regions involved in cognition (Creutzfeldt-Jakob disease, CJD), motor control (Gerstmann-Sträussler-Scheinker syndrome, GSS), or sleep and autonomic functions (fatal familial insomnia, FFI).  Each of these diseases is caused by the inheritance of a different mutation in the gene encoding the prion protein, PrP.   Importantly, since each of these mutations is expressed from the same place in the genome, there are no expression pattern differences.

In order to model this set of diseases we mutated the mouse’s PrP gene in a manner that maintains its native position in the genome.  We found that “knock-in” mice expressing mutations linked to CJD or FFI develop clinical signs and neuropathological changes remarkably similar to the human diseases but very different from each other.  Even more remarkably, the spontaneous disease in these mice was transmitted to mice not expressing disease-causing mutations by transfer of brain material between animals. Not only does this result lend support to the prion disease hypothesis but it also gives us very high confidence that the protein misfolding events occurring in humans are being reproduced in these models.  This allelic series of mouse lines and other lines in development will be the focus of intensive experiments aimed at understanding the problem of selective vulnerability.  Experimental strategies will involve genome manipulation, behavioral and sleep studies, in vivo imaging, protein biochemistry, gene expression analyses, and studies of the spatial distribution of proteins and RNAs in brain slices.


Publications

Spontaneous generation of prion infectivity in fatal familial insomnia knock-in mice.

#Jackson WS, Borkowski AW, Faas H, Steele AD, King OD, Watson N, Jasanoff A, Lindquist S. Neuron 63, 438-450 (2009).
#Article covered in Nature Reviews Neuroscience 10, 694 (2009)

Context-dependent perturbation of neural systems in transgenic mice expressing a cytosolic prion protein.

*Faas H, *Jackson WS, Borkowski A, Wang X, Ma J, Lindquist S, Jasanoff A. Neuroimage, online (2009 Oct 14)
* authors contributed equally

Context dependent neuroprotective properties of prion protein (PrP).

Steele AD, Zhou Z, Jackson WS, Zhu C, Auluck P, Moskowitz MA, Chesselet MF, Lindquist S. Prion 3, 240-9 (2009).

Lymphotoxin-dependent prion replication in inflammatory stromal cells of granulomas.

Heikenwalder M, Kurrer MO, Margalith I, Kranich J, Zeller N, Haybaeck J, Polymenidou M, Matter M, Bremer J, Jackson WS, Lindquist S, Sigurdson CJ, Aguzzi A. Immunity 29, 998-1008 (2008).

Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease.

Steele AD, Hutter G, Jackson WS, Heppner FL, Borkowski AW, King OD, Raymond GJ, Aguzzi A, Lindquist S. Proc Natl Acad Sci U S A 105, 13626-31 (2008).

Illuminating aggregate heterogeneity in neurodegenerative disease.

Jackson WS & Lindquist S. Nat Methods 4, 1000-1 (2007).

Diminishing apoptosis by deletion of Bax or overexpression of Bcl-2 does not protect against infectious prion toxicity in vivo.

Steele AD, King OD, Jackson WS, Hetz CA, Borkowski AW, Thielen P, Wollmann R, Lindquist S. J Neurosci 27, 13022-7 (2007).

The power of automated high-resolution behavior analysis revealed by its application to mouse models of Huntington’s and prion diseases.

Steele AD, Jackson WS, King OD, Lindquist S. Proc Natl Acad Sci U S A 104, 1983-8 (2007).

Prion pathogenesis is independent of caspase-12.

Steele AD, Hetz C, Yi CH, Jackson WS, Borkowski AW, Yuan J, Wollmann RH, and Lindquist S. Prion 1, 1-5 (2007).

Intraflagellar transport is essential for endochondral bone formation.

Haycraft CJ, Zhang Q, Song B, Jackson WS, Detloff PJ, Serra R, Yoder BK. Development, 134, 307-16 (2007).

Nucleocytoplasmic transport signals affect the age at onset of abnormalities in knock-in mice expressing polyglutamine within an ectopic protein context.

Jackson WS, Tallaksen-Greene SM, Albin RL, Detloff PJ. Human Molecular Genetics 12, 1621-1629 (2003).

HPRT(CAG)146 mice: age of onset of behavioral abnormalities, time course of neuronal intranuclear inclusion accumulation, neurotransmitter marker alterations, mitochondrial function markers, and susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Tallaksen-Greene SM, Ordway JM, Crouse AB, Jackson WS, Detloff PJ, Albin RL. HPRT(CAG). Journal of Comparative Neurology 465, 205-219 (2003).

Neurological abnormalities in a knock-in mouse model of Huntington’s disease.

Lin CH, Tallaksen-Greene S, Chein WM, Cearley JA, Jackson WS, Crouse AB, Ren S, Li XJ, Albin RL, Detloff PJ. Human Molecular Genetics 10, 137-44 (2001).